DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Status
Claims 2-4, 7, 10, 17-20, 23-30, and 39-44 have been cancelled and claims 1, 13-14, 21-22, 32-33, and 35-36 have been amended, as requested in the amendment filed on 03/13/2026. Following the amendment, claims 1, 5-6, 8-9, 11-16, 21-22, and 31-38 are pending in the instant application.
Claims 8-9 and 12 stand as withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention in the Response filed 02/16/2024, there being no allowable generic or linking claim.
Claims 1, 5-6, 11, 13-16, 21-22, and 31-38 are under examination in the instant office action.
Claim Rejections - 35 USC § 112 - Withdrawn
Claims 1, 5-6, 11, 13-16, 21-22, and 31-38 were rejected under 35 USC § 112(b), second paragraph, as being indefinite. Applicant has amended claim 1 to remove the recitation of “the chromatography effluent”. Further with regard to claim 1, Applicant argues on Pages 6-8 of Remarks (03/13/2026) that the terms “the dynamic binding capacity” and “the partition coefficient” are clear and definite to one of ordinary skill in the art, specifically in view of the instant specification (see, for example, paragraphs 0075, 0088, 0303). Applicant has amended claims 13-14, 21-22, 32-33, and 35-36 to remove the recitation of “about”. In view of the instant claim amendments and further in view of Applicant’s arguments, the rejection(s) of claims 1, 5-6, 11, 13-16, 21-22, and 31-38 under 35 USC § 112(b), second paragraph, as being indefinite are withdrawn.
Claim Rejections - 35 USC § 103 - Maintained
Claims 1, 5-6, 11, 13-16, 21-22, and 31-38 stand as rejected under pre-AIA 35 U.S.C.
103(a) as being unpatentable over US 2013/0331554 A1 (previously cited on PTO-892; herein
after referred to as "Ladiwala") in view of non-patent literature published by Brown et. al.
(Biotechnol. Appl. Biochem., 2010, 56, 59-70; previously cited on PTO-892; herein after
referred to as "Brown") and non-patent literature published by Voitl et. al. (Journal of
Chromatography A, 2010, 1217, 5753-5760; previously cited on PTO-892; herein after referred
to as "Voitl").
Response to Arguments
On Pages 8-15 of Remarks, Applicant argues the following:
Figure 8 of Brown merely assesses the strength of binding of the antibody monomer, CHOP, and Gentamycin to better understand the hierarchy of binding strength to the chromatography material by using a linear gradient from 0 to 100% in NaCl and acetate; this neither involves nor contemplates an elution step wherein the eluate is collected for pooling with the eluate from the overload step. Further, Brown neither teaches nor provides any reason or motivation for a POSITA to specifically modify the method of Ladiwala involving "overload bind and elute" by collecting the fractions from both the overloading step and the elution step and pooling them together; Brown teaches that its "overloading" step is its "final purification step" and therefore a further elution step added to Ladiwala would be counterintuitive and destroy the intended purpose of Ladiwala' s method.
The rationale for combining Ladiwala and Brown is flawed and reflects the use of impermissible hindsight bias using Applicant's own disclosure as a roadmap; the Office has not articulated how the "overload bind and elute" method of Ladiwala "can be modified to preferentially bind impurities/contaminants to the chromatography method" without destroying its intended purpose; the entire purpose of Ladiwala's method is to preferentially bind the desired product to the chromatography material. Additionally, the Office has not articulated how the "overload bind and elute" method of Ladiwala "can be modified to preferentially bind impurities/contaminants to the chromatography method" such that the desired product flows through, is collected, and then the desired product is selectively eluted from the chromatography material, and both collections are then pooled with a reasonable expectation of achieving high yield and purity.
There is no reason or motivation provided anywhere in Ladiwala or Brown that would lead a POSITA to abandon the "overload bind and elute" method of Ladiwala by specifically modifying it to achieve two separate technical effects: (1) overloading the composition onto a recited chromatography material under conditions such that the antibody preferentially flows through while the contaminants bind; and (2) eluting the antibody from the chromatography material under the recited conditions such that contaminants remain bound to the chromatography material.
There is a lack a reasonable expectation of how reversing the methodology of Ladiwala to selectively bind contaminants and then perform a subsequent elution step would have a reasonable expectation of resulting in an enhanced or increased concentration of a desired product. The assessment of binding strengths in Figure 8 of Brown neither teaches nor suggests the substantial modifications would need to be made to Ladiwala's method to arrive at the present claims, let alone with a reasonable expectation of success.
A POSITA would have no reason or motivation to specifically modify the method of Ladiwala to arrive at the recited overload step and the recited eluting step, and, thus, would likewise lack any reason or motivation to specifically endeavor to arrive at the recited elution buffer having a lower conductivity than the loading buffer, let alone with a reasonable expectation of success.
The Examples (i.e., Examples 5-10) of the present application demonstrates that the claimed OEC mode achieves unexpected results by, inter alia, demonstrating that the recited conditions can be used such that chromatography effluent from the recited overload step of a) can be pooled with the recited eluting step of b) and result in high yield, high purity, and high volume processing, which is highly advantageous, especially for commercial manufacturing. The claimed method reflects a substantial departure from the method of Ladiwala; only with the benefit of impermissible hindsight bias could a POSITA have a reasonable expectation that modifying the method of Ladiwala such that (1) instead of the desired product preferentially binding and the contaminants/undesired product flowing through, the opposite occurs, and (2) a new elution step is subsequently introduced, would result in high yield, high purity, and high volume processing in a single mode.
Applicant’s arguments have been fully considered, but are deemed not persuasive.
With regard to the arguments above, the following are noted:
Ladiwala is directed to a method for enhancing or increasing the concentration of biological product in a final mixture, utilizing an “overload bind and elute” mode of operation wherein biological product is allowed to contact a chromatography medium (or other matrix) at a concentration or in an amount which exceeds the static or the dynamic binding capacity of the chromatography medium (or other matrix). Notably, during the overload and bind step, biological product having a selected characteristic (such as a high overall net-negative charge or a high sialic acid content) preferentially binds to the chromatography medium (or other matrix) while biological product (as well as other impurities) not having the selected characteristic, or having less of the selected characteristic (such as biological product having a lower overall net negative charge or a lower sialic acid content) is excluded or separated from the medium (or matrix); subsequent to the overload and bind step, the bound target product is eluted (or otherwise dissociated or separated) from the chromatography medium (or other matrix) and recovered such that the biological product mixture obtained has been enriched with a higher concentration of product having the selected (target) characteristic compared to the product mixture prior to application of the overload bind and elute purification step. Ladiwala teaches a method for product (e.g., antibody) enrichment comprising an “overload bind and elute” mode of operation wherein a composition/mixture in a loading buffer is loaded onto a column (e.g., mixed mode, anion exchange, hydrophobic, or affinity) in excess of the dynamic binding capacity for the desired product and the desired product is subsequently eluted with an elution buffer while contaminants/undesired products remain on the column; the amount of product recovered in the final mixture can be about 80% and the biological products targeted by the method can be increased compared to the initial mixture by at least 90% (in reference to the eluate from the overload and elute steps).
Brown teaches overloading of ion-exchange membrane adsorbers, a form of frontal chromatography, as the final purification step in the production of mAbs (monoclonal antibodies) produced from CHO (Chinese-hamster ovary) cells wherein the preferential binding of impurities over antibody product was exploited such that impurities were retained on the membrane adsorbers while there was breakthrough of purified antibodies. Thus, Brown teaches that while methods wherein antibodies are retained have been demonstrated to be successful, methods of overload chromatography in cases of antibody purification wherein it is desired that impurities preferentially bind compared to the antibody, are also successful. Brown further discloses, generally, fraction collection during gradient elution, wherein the data of Brown Figure 8 summarizes the binding properties and elution profiles of each component of the initial mixture from which antibody was to be purified.
The Voitl reference is purely relied upon to establish that determining buffer compositions for the elution of target products (e.g., eluting antibody from different chromatography materials) was well understood and routine in the art, such that that the column utilized, binding capacity, partition coefficient, pH, and conductivity were recognized as antibody purification variables which achieve a recognized result; Applicant has provided no specific argument against the Voitl reference.
As indicated in the previous Office Action (12/17/2025), from the teachings of Brown and Ladiwala, it would have been obvious to one of ordinary skill in the art to use the “overload bind and elute” method of Ladiwala wherein an antibody is loaded onto a chromatography column (selected based on the property to be exploited for purification) in excess of the dynamic binding capacity for said antibody, wherein the method could be modified, as suggested by Brown, such that the impurities of the initial loading mixture preferentially bind the chromatography matrix (i.e., sufficiently pure antibody is part of the eluate of the overload step) wherein an elution step may then be performed such that an elution buffer is selected wherein any residual antibody bound to the chromatography matrix is selectively eluted while undesired contaminants remain bound to the column. Ladiwala and Brown are both directed to overload chromatography as methods of antibody purification, with Ladiwala disclosing overload and elute methods wherein antibodies are preferentially bound to the chromatography material, and Brown specifically indicates that binding contaminant to a chromatography material is successful for antibody purification. Brown further teaches individual elution profiles of antibody and impurities with a gradient elution, wherein the different components preferentially elute at different buffer compositions throughout the gradient elution. Ladiwala specifically indicated selecting elution buffers such that any bound target protein preferentially elutes while impurities remain bound to the column. From these teachings it would have been within the purview of one having ordinary skill in the art that, in addition to antibody obtained during the overloading step using the method of Brown, sufficiently purified antibody may also be obtained during an additional elution step, as some antibody may still be bound to the chromatographic material, and it would be desirable to pool as much sufficiently pure product (i.e., eluate from the overload step and eluate from an elution step) as possible to maximize recovery.
Thus, the modification of Ladiwala based on the teachings of Brown does not destroy the intended purpose of Ladiwala; the intended purpose of Ladiwala is to enrich/purify a desired product from a mixture that further comprises undesired product/contaminants, and the teachings of Brown specifically indicate that such a purpose is still achieved, even if impurities are preferentially bound to the chromatography matrix as opposed to preferentially binding antibodies as disclosed by Ladiwala. It would be within the purview of one having ordinary skill in the art that under the mode of operation of Brown, in addition to antibody obtained during the overloading step, sufficiently purified antibody may also be obtained during the elution step and it would be desirable to pool as much sufficiently pure product as possible. While the Ladiwala reference teaches a method of enriching a biological product, comprising an “overload bind and elute” mode of operation, which teaches preferentially binding the biological product of interest (e.g., mAb) to the chromatography material, Brown suggests that such a method can be modified to preferentially bind impurities/contaminants to the chromatography material instead, with a reasonable expectation of success.
Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).
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A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also > Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005)(reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); < Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). Furthermore, “[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Ladiwala specifically indicates that methods of the invention can be adapted and applied to the separation/purification of biological products based on any number of physical, biological, and/or chemical characteristics (Paragraph 0038). The method of Ladiwala may therefore be applied in a variety of applications wherein the property/properties utilized for separation/purification may be any given property unique to the desired product compared to undesired products/contaminants. Brown discloses an alternative mode of operation to Ladiwala that exploits binding properties of antibodies versus contaminants. Thus, modification of the methods of Ladiwala and/or Brown to exploit different properties for purification of a given desired product from undesired products/contaminants is within the purview of one having ordinary skill in the art.
It is noted that “[a]ny judgement on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” In re McLaughlin 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). Ladiwala indicates that an advantage of utilizing the “overload bind and elute” mode of operation is that the biological product mixture obtained has been enriched with a higher concentration of product having the selected (target) characteristic compared to the product mixture prior to application of the overload bind and elute purification step (Paragraph 0037). Furthermore, Brown discloses that overload chromatography is an effective application of a purification technology that is uniquely advantageous to membranes, as it lends itself to the large volume pools typically encountered downstream of Protein A, wherein overall the results of the study show that this approach can be used as a rapid, high-yielding, final purification step for the production of mAbs (Page 69, Column 2, Paragraph 2). Thus, modification of Ladiwala based on the teachings of Brown, and Voitl, would still be expected to result in high yield and high purity mAbs, wherein high-volume processing is also a viable option; as such the results/features observed in instant Examples 5-10 are not considered “unexpected”. Particularly, the combination of teachings from Ladiwala and Brown, particularly as pertains to the pooling step instantly claimed, would be expected to yield and improved purification method because the amount of product recovered that is purified would be increased; residual antibody that may have bound the chromatography matrix can be specifically collected at a high degree of purity during an elution step and it would be within the purview of one having ordinary skill in the art to combine the product from said elution step with the purified product of the overload step in order to increase the overall yield of purified product (which is the intended purpose of the methods of both Ladiwala and Brown).
Additionally, obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). Both Ladiwala and Brown disclose the use of overload and elute methods for the purification/enrichment of biological products (e.g., antibodies) wherein undesired products/contaminants can be selectively removed utilizing column chromatography, and thus the combination of teachings would be reasonably expected to yield a method of purifying an antibody with a reasonable expectation of success as established by both Ladiwala and Brown; the selected mode of operation does not change the outcome of obtaining enriched/purified product and as such there is reasonable expectation of success in combining the teachings of Brown and Ladiwala in view of the teachings of Voitl. Furthermore, the active steps of the instantly claimed method are rendered obvious by Ladiwala, Brown, and Voitl; the fact that Applicant has recognized another advantage which would flow naturally from performing the active steps of the instantly claimed method following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Furthermore, it is noted that the rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992); see also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); Ex parte Clapp, 227 USPQ 972 (Bd. Pat. App. & Inter. 1985) (examiner must present convincing line of reasoning supporting rejection); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP 2144(I).
As such, the rejection of claims 1, 5-6, 11, 13-16, 21-22, and 31-38 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Ladiwala, Brown, and Voitl is maintained.
Conclusion
Claims 1, 5-6, 8-9, 11-16, 21-22, and 31-38 are pending. Claims 8-9 and 12 are withdrawn. Claims 1, 5-6, 11, 13-16, 21-22, and 31-38 are rejected. No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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